Epigenetic aspects of genotoxic and non-genotoxic hepatocarcinogenesis: studies in rodents

Abstract

Hepatocellular carcinoma, which is one of the most prevalent life-threatening human cancers, is showing an increased incidence worldwide. Recent evidence indicates that the development of hepatocellular carcinoma is associated with not only genetic alterations, but also with profound epigenetic changes. This review summarizes the current knowledge about epigenetic alterations during rodent hepatocarcinogenesis, considers the similarities and differences in epigenetic effects of genotoxic and non-genotoxic rodent liver carcinogens, and discusses the possible role of these effects in the causality of liver tumor development.

Fig. 1

An integrated view of the role of epigenetic dysregulation in hepatocarcinogenesis. Genotoxic or non-genotoxic insults injure many liver cells triggering changes in the cellular epigenome. Alterations in epigenetic mechanisms lead to early disruption of homeostasis in liver cells characterized by a loss in the balance between cell proliferation and apoptosis, activation of DNA repetitive sequences in the genome, loss of genomic and chromosomal stability, and aberrant expression of genomic information. This results in the emergence of the population of epigenetically reprogrammed proliferating cells with a growth advantage and high potential for activation of a mutator phenotype and, consequently, leads to malignant cell transformation.